1. Field of the Invention
This invention relates, generally, to the delivery of pharmaceutical agents. More particularly, it relates to dermal delivery of active pharmaceutical agent(s) by surface modified multilayered nanostructures penetrating the stratum corneum.
2. Description of the Prior Art
Dermal delivery of pharmaceutical agent(s) has several advantages over conventional oral and intravenous dosage forms for treatment of skin diseases when the target site is present in the deep epidermis. Delivering pharmaceutical agents dermally avoids the first pass effect, allows local delivery of the drug, minimizes a patient's pain and avoids excessive drug dumping into the blood associated with other dosage forms (B. W. Barry, Novel mechanisms and devices to enable successful transdermal drug delivery, Eur. J. Pharm. Sci., 14 (2001) 101-114). Dermal delivery is best suited for skin diseases and disorders, including: fungal, bacterial and viral infections; inflammation associated with rheumatoid arthritis, Crohn's disease, multiple sclerosis, eczema and psoriasis; tumor and dry skin; dermatitis and skin cancers like melanoma; etc. It is also desirable to deliver many cosmetic and active pharmaceutical agent(s) to have anti-wrinkle and/or anti-aging effects.
To treat such skin diseases and disorders, the effective delivery of active pharmaceutical agent(s) into the deeper layers of skin is needed. However, the stratum corneum, or foremost layer of skin, acts as the main barrier between the body and the environment, thereby limiting the delivery of many drugs (B. W. Barry, Novel mechanisms and devices to enable successful transdermal drug delivery, Eur. J. Pharm. Sci., 14 (2001) 101-114; K. Moser et al., Passive skin penetration enhancement and its quantification in vitro, Eur. J. Pharm. Biopharm., 52 (2001) 103-112). To deliver sufficient amount of the active pharmaceutical agent(s) into the deeper layers of skin, many techniques have been introduced and performed, for example chemical enhancement including permeation enhancers and prodrug design (K. B. Sloan, Prodrugs for dermal delivery, Adv. Drug Deliv. Rev., 3 67-101; J. Drustrup et al., Utilization of prodrugs to enhance the transdermal absorption of morphine, Int. J. Pharm., 71 (1991) 105-116), physical enhancement including use of microneedles (M. R. Prausnitz, Microneedles for transdermal drug delivery, Adv. Drug Deliv. Rev., 56 (2004) 581-587), ionotophoresis (Y. N. Kalia et al., Iontophoretic drug delivery, Adv. Drug Deliv. Rev., 56 (2004) 619-658), phonophoresis, thermal modulation, magnetic modulation, mechanical modulation, ultrasound (N. B. Smith, Applications of ultrasonic skin permeation in transdermal drug delivery, Expert Opin. Drug Deliv., 5 (2008) 1107-1120), and electroporation (A. R. Denet et al., Skin electroporation for transdermal and topical delivery, Adv. Drug Deliv. Rev., 56 (2004) 659-674). However, each of these techniques has its respective problems in terms of toxicity and therapeutic feasibility.
Nanotechnology is an advanced and non-invasive technique adopted for improving skin permeation of active pharmaceutical agent(s) (T. W. Prow et al., Nanoparticles and microparticles for skin drug delivery, Adv. Drug Deliv. Rev., 63 (2011) 470-91). Various biocompatible and biodegradable synthetic or semi-synthetic polymers, including polylactic acid (PLA) (F. Rancan et al., Investigation of polylactic acid (PLA) nanoparticles as drug delivery systems for local dermatotherapy, Pharm. Res., 26 (2009) 2027-2036), poly(lactic-co-glycolic acid) (PLGA) (J. Lademann et al., Nanoparticles—an efficient carrier for drug delivery into the hair follicles, Eur. J. Pharm. Biopharm., 66 (2007) 159-164), poly(ε-caprolactone) (R. Alvarez-Roman et al., Biodegradable polymer nanocapsules containing a sunscreen agent: preparation and photoprotection, Eur. J. Pharm. Biopharm., 52 (2001) 191-195), and chitosan (C. Colonna et al., Ex vivo evaluation of prolidase loaded chitosan nanoparticles for the enzyme replacement therapy, Eur. J. Pharm. Biopharm., 70 (2008) 58-65) have shown promise in dermal delivery, including topical and transdermal drug delivery.
Several studies have been reported on preparation and characterization of polymeric biodegradable nanoparticles as skin delivery systems due to their potential usefulness in increasing efficacy, reducing enzymatic degradation, controlling release rates and high encapsulation efficiency (F. Rancan et al., Investigation of polylactic acid (PLA) nanoparticles as drug delivery systems for local dermatotherapy, Pharm. Res., 26 (2009) 2027-2036; J. Lademann et al., Nanoparticles—an efficient carrier for drug delivery into the hair follicles, Eur. J. Pharm. Biopharm., 66 (2007) 159-164; R. Alvarez-Roman et al., Biodegradable polymer nanocapsules containing a sunscreen agent: preparation and photoprotection, Eur. J. Pharm. Biopharm., 52 (2001) 191-195; R. Alvarez-Roman et al., Enhancement of topical delivery from biodegradable nanoparticles, Pharm. Res., 21 (2004) 1818-1825; X. Wu et al., Disposition of nanoparticles and an associated lipophilic permeant following topical application to the skin, Mol. Pharm., 6 (2009) 1441-1448).
The most commonly used polymer for the preparation of these carriers is PLGA. PLGA is well known to be safe, biocompatible, non-toxic and is restorable through natural pathways (J. Panyam et al., Biodegradable nanoparticles for drug and gene delivery to cells and tissue, Adv. Drug Deliv. Rev., 55 (2003) 329-347). Further, chitosan is a promising and often used candidate for surface modification due to its biocompatibility (P. P. Shah et al., Influence of chitosan crosslinking on bitterness of mefloquine hydrochloride microparticles using central composite design, J. Pharm. Sci., 98 (2009) 690-703) and positive charge (D. Vllasaliu et al., Tight junction modulation by chitosan nanoparticles: comparison with chitosan solution, Int. J. Pharm., 400 (2010) 183-193). Studies have shown that chitosan and its derivatives interact with the negative charge of SC resulting in opening of tight junctions (S. F. Taveira et al., Effect of the iontophoresis of a chitosan gel on doxorubicin skin penetration and cytotoxicity, J. Control Release, 134 (2009) 35-40; W. He et al., Study on the mechanisms of chitosan and its derivatives used as transdermal penetration enhancers, Int. J. Pharm., 382 (2009) 234-243; W. He et al., Transdermal permeation enhancement of N-trimethyl chitosan for testosterone, Int. J. Pharm., 356 (2008) 82-87), thus acting as a permeation enhancer.
Though the polymer-based nanoparticles offer advantage of controlled and sustained drug release with greater stability (R. Alvarez-Roman et al., Enhancement of topical delivery from biodegradable nanoparticles, Pharm. Res., 21 (2004) 1818-1825; X. Wu et al., Disposition of nanoparticles and an associated lipophilic permeant following topical application to the skin, Mol. Pharm., 6 (2009) 1441-1448; S. Kuchler et al., Nanoparticles for skin penetration enhancement—a comparison of a dendritic core-multishell-nanotransporter and solid lipid nanoparticles, Eur. J. Pharm. Biopharm., 71 (2009) 243-250), they have not been explored to a greater extent for dermal delivery.
Moreover, studies have indicated that nanoparticles do not cross the stratum corneum but rather permeate into the layers of the stratum corneum and release the drug in a controlled manner into the upper epidermis, followed by passive diffusion to further skin layers. This limits the amount of active pharmaceutical agent(s) that actually reaches the target region.
Nanoparticles have also been noted to accumulate in skin furrows and permeate through hair follicles with their associated sebaceous glands, rather than crossing the stratum corneum (SC) (F. Rancan et al., Investigation of polylactic acid (PLA) nanoparticles as drug delivery systems for local dermatotherapy, Pharm. Res., 26 (2009) 2027-2036). Thus, the amount of active pharmaceutical agent(s) actually reaching the target site is very limited. (R. R. Patlolla et al., Translocation of cell penetrating peptide engrafted nanoparticles across skin layers, Biomaterials, 31 (2010) 5598-5607; A. Vogt et al., 40 nm, but not 750 or 1,500 nm, Nanoparticles Enter Epidermal CD1a+ Cells after Transcutaneous Application on Human Skin, J. Invest. Dermatol., 126 (2006) 1316-1322; R. Alvarez-Roman et al., Skin penetration and distribution of polymeric nanoparticles, J. Control Release, 99 (2004) 53-62). In addition, only a small amount of active pharmaceutical agent(s) permeates into the hair follicle in the first place.
Many scientists have reports use of bilayered polymeric nanoparticles, such as chitosan modified poly(D,L-lactide-co-glycolide) (PLGA) copolymer nanoparticles for improving DNA and siRNA delivery into the cells (N. Nafee et al., Chitosan-coated PLGA nanoparticles for DNA/RNA delivery: effect of the formulation parameters on complexation and transfection of antisense oligonucleotides. Nanomedicine 3 (2007) 173-183; M. N. Ravikumar et al., Preparation and characterization of cationic PLGA nanospheres as DNA carriers. Biomaterials 25 (2004) 1771-1777).
Similarly, Zhou et al. reports use of multilayered nanoparticles, alginate and chitosan to coat PLGA nanoparticles for folic acid binding to achieve selective cell targeting. The surface of these multilayered nanoparticles is modified by folic acid through polyethylene glycol. These folic acid-modified multilayered nanoparticles showed improved cell uptake (J. Zhou et al., Layer by layer chitosan/coatings on poly(lactide-co-glycolide) nanoparticles for antifouling protection and folic acid binding to achieve selective cell targeting. J. Colloid Interface Sci. 345 (2010) 241-247).
Jain et al. reported use of water-dispersible oleic acid-poloxamer-coated iron oxide magnetic nanoparticle formulation to load high doses of water insoluble anticancer drug. In this study, oleic acid was used to dissolve the water-insoluble anticancer drug, and the surface of the magnetic nanoparticles was modified by poloxamers. The role of oleic acid was to keep iron oxide magnetic core inside the co-polymer matrix. These magnetic nanoparticles showed sustained intracellular retention and dose-dependent antiproliferative effect in breast and cancer cell lines (T. K. Jain et al., Iron oxide nanoparticles for sustained delivery of anticancer agents. Mol. Pharm. 2 (2005) 194-205).
A study has also reported use of bilayered polymeric nanoparticles for transdermal delivery of DNA and epidermal Langerhans cells tracking. However, this study used gene gun bombardment technique for delivery of DNA into the deeper skin layers (P. W. Lee et al. Multifunctional core-shell polymeric nanoparticles for transdermal DNA delivery and epidermal Langerhans cells tracking Biomaterials 31 (2010) 2425-2434). This gene gun bombardment technique is an aggressive approach for dermal delivery and requires special assistance.
Fatty acids (FA) are known to be chemical permeation enhancers and widely used in commercial formulations. FA interacts with, induces and modifies the lipid domains within the stratum corneum bilayer lipids (B. W. Barry, Mode of action of penetration enhancers in human skin, J. Control Release, 6 (1987) 85-97). Electron microscopic study has suggested that lipid domain is stimulated within the SC bilayer lipids upon exposure to oleic acid (OA), a well-known fatty acid (H. Tanojo et al., In vitro human skin barrier perturbation by oleic acid: Thermal analysis and freeze fracture electron microscopy studies, Thermochimica Acta, 293 (1997) 77-85). The formation of such induced pools provides permeability defects within the bilayer lipids, thus facilitating permeation through the membrane into the deeper layers of skin.
Furthermore, with increasing complexities of these skin-related diseases and disorders, application of only one active pharmaceutical agent does not always treat the disease or disorder effectively. In addition, to achieve a therapeutic response, higher doses of a drug are required, resulting in unwanted side effects. To overcome this problem, a combination therapy is used to treat various disease conditions because the combination of disease modifying drugs can act through different pathways and offer possibility of synergistic or additive effects (C. Zegpi et al., The effect of opioid antagonists on synergism between dexketoprofen and tramadol, Pharmacol. Res., 60 (2009) 291-295), thus minimizing drug induced toxicities associated with higher dose of individual drug. However, the art has not shown any studies attempting to deliver more than one active pharmaceutical agent dermally using surface modified multilayered nano structures.
Accordingly, what is needed is the effective simultaneous delivery of two or more active pharmaceutical agent(s) into the deeper layers of skin without use of special techniques, such as gene gun bombardment. However, in view of the art considered as a whole at the time the present invention was made, it was not obvious to those of ordinary skill how the art could be advanced.
While certain aspects of conventional technologies have been discussed to facilitate disclosure of the invention, Applicants in no way disclaim these technical aspects, and it is contemplated that the claimed invention may encompass one or more of the conventional technical aspects discussed herein.
The present invention may address one or more of the problems and deficiencies of the prior art discussed above. However, it is contemplated that the invention may prove useful in addressing other problems and deficiencies in a number of technical areas. Therefore, the claimed invention should not necessarily be construed as limited to addressing any of the particular problems or deficiencies discussed herein.
In this specification, where a document, act or item of knowledge is referred to or discussed, this reference or discussion is not an admission that the document, act or item of knowledge or any combination thereof was at the priority date, publicly available, known to the public, part of common general knowledge, or otherwise constitutes prior art under the applicable statutory provisions; or is known to be relevant to an attempt to solve any problem with which this specification is concerned.